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Novel Coumarin Containing Dithiocarbamate Derivatives as Potent α- Glucosidase Inhibitors for Management of Type 2 Diabetes

Author(s):

Marjan Mollazadeh, Maryam Mohammadi-Khanaposhtani, Yousef Valizadeh, Afsaneh Zonouzi, Mohammad Ali Faramarzi, Mitra Kiani, Mahmood Biglar, Bagher Larijani, Haleh Hamedifar , Mohammad Mahdavi * and Mir Hamed Hajimiri   Pages 1 - 9 ( 9 )

Abstract:


Background: α-Glucosidase is a hydrolyze enzyme that plays a crucial role in degradation of carbohydrates and starch to glucose. Hence, α-glucosidase is an important target in the carbohydrate mediated diseases such as diabetes mellitus.

Objective: In this study, novel coumarin containing dithiocarbamate derivatives 4a-n were synthesized and evaluated against α-glucosidase in vitro and in silico.

Methods: These compounds were obtained of reaction between 4-(bromomethyl)-7-methoxy-2H-chromen-2-one 1, carbon disulfide 2, and primary or secondary amines 3a-n in the presence potassium hydroxide and ethanol at room temperature. In vitro α-glucosidase inhibition and kinetic study of these compounds were performed. Furthermore, docking study of the most potent compounds was also performed by Auto Dock Tools (version 1.5.6).

Results: Obtained results showed that all the synthesized compounds exhibited prominent inhibitory activities (IC50 = 85.0 ± 4.0-566.6 ± 8.6 μM) in comparison to acarbose as standard inhibitor (IC50 = 750.0 ± 9.0 µM). Among them, secondary amine derivative 4d with pendant indole group was the most potent inhibitor. Enzyme kinetic study of the compound 4d revealed that this compound compete with substrate to connect to the active site of α-glucosidase and therefore is a competitive inhibitor. Also, molecular docking study predicted that this compound as well interacted with α-glucosidase active site pocket.

Conclusion: Our results suggest that the coumarin-dithiocarbamate scaffold can be a promising lead structure for design potent α-glucosidase inhibitors for treatment of type 2 diabetes.

Keywords:

Anti-diabetic activity, α-Glucosidase, Molecular docking, Coumarin, Dithiocarbamate, In vitro evaluation

Affiliation:

School of Chemistry, College of Science, University of Tehran, Tehran, Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, School of Chemistry, College of Science, University of Tehran, Tehran, Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, CinnaGen Medical Biotechnology Research Center, Alborz University of Medical Sciences, Karaj, Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Nano Alvand Company, Avicenna Tech Park, Tehran University of Medical Sciences, Tehran



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